There have been rapid advances in our understanding of neurophysiologic changes that underlie the generation and maintenance of hypersensitivity states in animals, and these are presumed to underlie the phenomena of spontaneous pain, hyperalgesia, and allodynia in patients with pain. The distinction between 'acute' and 'chronic' pain is becoming blurred, as one can demonstrate many of these 'chronic' phenomena in animal models of brief injury (e.g., paw incision, intradermal capsaicin injection). Despite these advances, clinical application or even testing of these concepts has lagged far behind. This Center's goal is to prove mechanisms that underlie altered analgesic drug responses following generation of hypersensitivity states in the laboratory and to test the resultant hypotheses and their clinical relevance in humans. Five Projects are proposed, examining (I) mechanisms behind the shift in spinal circuitry activated by alpha2-adrenergic agonists and reduction in opioid agonist efficacy following peripheral nerve injury, (II) regional spinal opioid ligand efficacy using a functional G-protein activation assay and changes in efficacy in hypersensitivity and chronic drug exposure, (III) hormonal influences which determine the large sex difference observed in analgesic response to cholinergic agents, (IV) patterns of self-administration of opioids in animals with and without hypersensitivity following peripheral nerve injury, and (V) human relevance of hypotheses generated by (I-IV). Laboratory efforts are linked in complex, overlapping fashion, and are supported by an Animal and General Research Services Core, which includes a much needed model development section, and an Administrative Core, which will encourage discussion, sharing, and focus. Perhaps most important to this Center is application of unique pharmacologic tools at this institution and expertise in trial design to assemble, through Project V, 4 key clinical studies to test important translational and methodological hypotheses, including systemic opioid efficacy in chronic pain, role of hypersensitivity in postoperative and chronic pain, and predictive value of pharmacologic testing in volunteers to pain in patients. Thus, this Center fills an important void in bringing togther clinicians and laboratory scientists to explore novel therapeutics and mechanisms of pain.